Linda M. Graham, M.D.
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Synthetic grafts used for vascular bypasses have limited long-term patency. Inadequate endothelial cell ingrowth contributes to their long-term thrombogenicity, and smooth muscle cell accumulation with matrix deposition can progress to intimal hyperplasia and graft failure. Oxidized lipids accumulate in prosthetic grafts and contribute to cellular dysfunction. They also inhibit endothelial cell migration in vitro by increasing reactive oxygen species production, altering cell membrane fluidity, disrupting cytoskeletal components, and opening calcium channels.
Oxidized lipids also contribute to smooth muscle cell dysfunction on prosthetic grafts. The graft smooth muscle cells acquire a synthetic, proliferative phenotype, and, compared with aortic smooth muscle cells, produce higher levels of growth factors and collagen. Oxidized lipids stimulate growth factor and collagen secretion, regulating their production at transcriptional and post-transcriptional levels.
Our research is exploring the pathways involved. A better understanding of the changes in cell function on prosthetic grafts, and the mechanisms responsible, will allow development of mechanism-based therapies to improve graft patency.
The long-term goal of our research is improvement in the healing of bypass grafts or arteries after balloon angioplasty and stenting. We are investigating how oxidized lipids (a potentially dangerous type of cholesterol that the body sometimes produces) contribute to the build-up of scar tissue and prevent endothelial cells (cells that normally line blood vessels) from moving into an area of injury or onto a bypass graft. The results of these studies guide our development of treatments to promote endothelial cell healing and limit scarring after procedures on blood vessels to the heart and legs.
Putta P, Smith AH, Chaudhuri P, Guardia-Wolff R, Rosenbaum MA, Graham LM. Activation of the cytosolic calcium-independent phospholipase A2 β isoform contributes to TRPC6 externalization via release of arachidonic acid. J Biol Chem. 2021 Oct;297(4):101180. doi: 10.1016/j.jbc.2021.101180. Epub 2021 Sep 10. PMID: 34509476; PMCID: PMC8498464.
Run Shi, Shanshan Gao, Jie Zhang, Jiang Xu, Linda M Graham, Xiaowen Yang, Chaoyang Li. Collagen prolyl 4-hydroxylases modify tumor progression. Acta Biochim Biophys Sin (Shanghai). 2021 May 19;gmab065. doi: 10.1093/abbs/gmab065.
Chaudhuri P, Smith AH, Graham LM, Rosenbaum MA. Inhibition of P110α and P110δ catalytic subunits of PI3 kinase reverses impaired arterial healing after injury in hypercholesterolemic male mice. Am J Physiol Cell Physiol. 2021 Mar 10. doi: 10.1152/ajpcell.00600.2020. Online ahead of print. PMID: 33689479
Chaudhuri P, Smith AH, Putta P, Graham LM, Rosenbaum MA. P110α and P110δ catalytic subunits of PI3 kinase regulate lysophosphatidylcholine-induced TRPC6 externalization. Am J Physiol Cell Physiol. 2021 May 1;320(5):C731-C741. doi: 10.1152/ajpcell.00425.2020. Epub 2021 Feb 24. PMID: 33625929
Smith AH, Putta P, Driscoll EC, Chaudhuri P, Birnbaumer L, Rosenbaum MA, Graham LM. Canonical transient receptor potential 6 channel deficiency promotes smooth muscle cells dedifferentiation and increased proliferation after arterial injury. JVS Vasc Sci. 2020;1:136-150. doi: 10.1016/j.jvssci.2020.07.002. Epub 2020 Jul 28. PMID: 33554153
Shi R, Gao S, Smith AH, Li H, Shao M, Shangguan J, Zhang J, Xu J, Ye J, Graham LM, Li C. Superoxide-induced Type I collagen secretion depends on prolyl 4-hydroxylases. Biochem Biophys Res Commun. 2020 Sep 3;529(4):1011-1017. doi: 10.1016/j.bbrc.2020.07.002. Epub 2020 Jul 30. PMID: 32819558
Shi R, Hu W, Zhang Y, Gao S, Smith AH, Ye J, Cai L, Graham LM, Li C. Ascorbate inducible N259 glycans on prolyl 4-hydroxylase subunit α1 promote hydroxylation and secretion of type I collagen. Cell Mol Life Sci. 2019 Sep;76(17):3449-3464. doi: 10.1007/s00018-019-03081-w. Epub 2019 Mar 27.PMID: 30919021
Chaudhuri P, Rosenbaum MA, Birnbaumer L, Graham LM. Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine-induced TRPC5 externalization. Am J Physiol Cell Physiol. 2017 Nov 1;313(5):C541-C555. doi: 10.1152/ajpcell.00028.2017. Epub 2017 Aug 23. PMID: 28835433
Chaudhuri P, Rosenbaum MA, Sinharoy P, Damron DS, Birnbaumer L, Graham LM. Membrane translocation of TRPC6 channels and endothelial migration are regulated by calmodulin and PI3 kinase activation. Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2110-5. doi: 10.1073/pnas.1600371113. Epub 2016 Feb 8. PMID: 26858457
Rosenbaum MA, Chaudhuri P, Abelson B, Cross BN, Graham LM. Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress. Atherosclerosis. 2015 Aug;241(2):709-15. doi: 10.1016/j.atherosclerosis.2015.06.018. Epub 2015 Jun 18. PMID: 26125413
Bhak RH, Wininger M, Johnson GR, Lederle FA, Messina LM, Ballard DJ, Wilson SE; Aneurysm Detection and Management (ADAM) Study Group. Factors associated with small abdominal aortic aneurysm expansion rate. JAMA Surg. 2015 Jan;150(1):44-50. doi: 10.1001/jamasurg.2014.2025. PMID: 25389641
Rosenbaum MA, Chaudhuri P, Graham LM. Hypercholesterolemia inhibits re-endothelialization of arterial injuries by TRPC channel activation. J Vasc Surg. 2015 Oct;62(4):1040-1047.e2. doi: 10.1016/j.jvs.2014.04.033. Epub 2014 May 10. PMID: 24820897 Free PMC article.
Rosenbaum MA, Chaudhuri P, Abelson B, Cross BN, Graham LM. Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress. Atherosclerosis. 241:709-715, 2015, PMCID: PMC4529116
Rosenbaum MA, Chaudhuri P, Graham LM. Hypercholesterolemia inhibits reendothelialization of arterial injuries through TRPC channel activation. J Vasc Surg 62(4): 1040-1047, 2015. PMCID: PMC4226809
King AP, Abelson JL, Gholami B, Upchurch G, Henke P, Graham L, Liberzon I. Pre-surgical psychological and neuroendocrine predictors of psychiatric morbidity following major vascular surgery: a prospective longitudinal study. Psychosomatic Medicine. 77(9) 993-1005, 2015. PMCID: PMC4643324
Chaudhuri P, Sinharoy P, Damron DS, Birnbaumer L, Graham LM. Membrane Translocation of TRPC6 Channels and Endothelial Migration are Regulated by Calmodulin and PI3 Kinase Activation. Proc Natl Acad Sci USA 113(8): 2110-2115, 2016. PMCID: PMC4776520
Rosenbaum MA, Miyazaki K, Graham LM. Hypercholesterolemia and oxidative stress inhibit endothelial healing after arterial injury. J Vasc Surg 55:489-496. 2012. PMCID: PMC3264759
Chaudhuri P, Rosenbaum MA, Birnbaumer L, Graham LM. Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine-induced TRPC5 externalization. Am J Physiol Cell Physiol 313(5):C541-C555, 2017. PMCID: PMC5792165
Shi R, Hu M, Zhang Y, Gao S, Smith AH, Ye J, Cai L, Graham LM, Li C. Ascorbate inducible N259 glycans on prolyl 4-hydoxylase subunit a1 promote hydroxylation and secretion of Type I collagen. Cell Mol Life Sci 76(17): 3449-3464, 2019. PMCID: PMC6698205
Chaudhuri P, Colles SM, Fox PL, Graham LM. Protein kinase Cδ-dependent phosphorylation of syndecan-4 regulates cell migration. Circ Res 97:674-681, 2005.
Miyazaki K, Colles SM, Graham LM. Impaired graft healing due to hypercholesterolemia is prevented by dietary supplementation with α-tocopherol. J Vasc Surg 48:986-993, 2008.
Chaudhuri P, Colles SM, Bhat M, Van Wagoner DR, Birnbaumer L, Graham LM. Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement. Mol Biol Cell 19:3203-3211, 2008.
Rosenbaum MA, Miyazaki K, Colles SM, Graham LM. Antioxidant therapy reverses impaired graft healing in hypercholesterolemic rabbits. J Vasc Surg 51:184-193, 2010.
Fan Y, Gong Y, Ghosh PK, Graham LM, Fox PL. Spatial coordination of actin polymerization and ILK-Akt2 activity during endothelial cell migration. Dev Cell. 2009 May;16(5):661-74. doi: 10.1016/j.devcel.2009.03.009. PMID: 19460343 Free PMC article.
Miyazaki K, Colles SM, Graham LM. Impaired graft healing due to hypercholesterolemia is prevented by dietary supplementation with alpha-tocopherol. J Vasc Surg. 2008 Oct;48(4):986-93. doi: 10.1016/j.jvs.2008.04.010. Epub 2008 Jun 30. PMID: 18585884 Free PMC article.
Chaudhuri P, Colles SM, Bhat M, Van Wagoner DR, Birnbaumer L, Graham LM. Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement. Mol Biol Cell. 2008 Aug;19(8):3203-11. doi: 10.1091/mbc.e07-08-0765. Epub 2008 May 21. PMID: 18495872 Free PMC article.
Liberzon I, Abelson JL, Amdur RL, King AP, Cardneau JD, Henke P, Graham LM. Increased psychiatric morbidity after abdominal aortic surgery: risk factors for stress-related disorders. J Vasc Surg. 2006 May;43(5):929-34. doi: 10.1016/j.jvs.2006.01.026. PMID: 16678685 Free article.
Patel R, Cardneau JD, Colles SM, Graham LM. Synthetic smooth muscle cell phenotype is associated with increased nicotinamide adenine dinucleotide phosphate oxidase activity: effect on collagen secretion. J Vasc Surg. 2006 Feb;43(2):364-71. doi: 10.1016/j.jvs.2005.10.032. PMID: 16476616 Free article.
Almahameed A, Latif AA, Graham LM. Managing abdominal aortic aneurysms: treat the aneurysm and the risk factors. Cleve Clin J Med. 2005 Oct;72(10):877-88. doi: 10.3949/ccjm.72.10.877. PMID: 16231685 Free article.
Chaudhuri P, Colles SM, Fox PL, Graham LM. Protein kinase Cdelta-dependent phosphorylation of syndecan-4 regulates cell migration. Circ Res. 2005 Sep 30;97(7):674-81. doi: 10.1161/01.RES.0000184667.82354.b1. Epub 2005 Sep 1. PMID: 16141413
van Aalst JA, Zhang DM, Miyazaki K, Colles SM, Fox PL, Graham LM. Role of reactive oxygen species in inhibition of endothelial cell migration by oxidized low-density lipoprotein. J Vasc Surg. 2004 Dec;40(6):1208-15. doi: 10.1016/j.jvs.2004.09.020. PMID: 15622376 Free article.
Absood A, Furutani A, Kawamura T, Graham LM. A comparison of oxidized LDL-induced collagen secretion by graft and aortic SMCs: role of PDGF. Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1200-6. doi: 10.1152/ajpheart.00228.2004. Epub 2004 May 13. PMID: 15142849 Free article.
Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Prevalence of abdominal aortic aneurysm and repair outcomes on the basis of patient sex: Should the timing of intervention be the same? J Thorac Cardiovasc Surg. 2004 Feb;127(2):325-8. doi: 10.1016/j.jtcvs.2003.10.022. PMID: 14762338 Free article. Review. No abstract available.
Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Outcome of carotid endarterectomy on the basis of patient sex: is there a difference? J Thorac Cardiovasc Surg. 2004 Feb;127(2):322-4. doi: 10.1016/j.jtcvs.2003.10.021. PMID: 14762337 Free article.
Harthun NL, Cheanvechai V, Graham LM, Freischlag JA, Gahtan V. Arterial occlusive disease of the lower extremities: do women differ from men in occurrence of risk factors and response to invasive treatment? J Thorac Cardiovasc Surg. 2004 Feb;127(2):318-21. doi: 10.1016/j.jtcvs.2003.10.020. PMID: 14762336 Free article.
Cheanvechai V, Harthun NL, Graham LM, Freischlag JA, Gahtan V. Incidence of peripheral vascular disease in women: is it different from that in men? J Thorac Cardiovasc Surg. 2004 Feb;127(2):314-7. doi: 10.1016/j.jtcvs.2003.10.019. PMID: 14762335 Free article
Vasanji A, Ghosh PK, Graham LM, Eppell SJ, Fox PL. Polarization of plasma membrane microviscosity during endothelial cell migration. Dev Cell. 2004 Jan;6(1):29-41. doi: 10.1016/s1534-5807(03)00397-6. PMID: 14723845 Free article.
van Aalst JA, Burmeister W, Fox PL, Graham LM. Alpha-tocopherol preserves endothelial cell migration in the presence of cell-oxidized low-density lipoprotein by inhibiting changes in cell membrane fluidity. J Vasc Surg. 2004 Jan;39(1):229-37. doi: 10.1016/s0741-5214(03)01038-3. PMID: 14718844 Free article.
Chaudhuri P, Colles SM, Damron DS, Graham LM. Lysophosphatidylcholine inhibits endothelial cell migration by increasing intracellular calcium and activating calpain. Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):218-23. doi: 10.1161/01.atv.0000052673.77316.01. PMID: 12588762
Ghosh PK, Vasanji A, Murugesan G, Eppell SJ, Graham LM, Fox PL. Membrane microviscosity regulates endothelial cell motility. Nat Cell Biol. 2002 Nov;4(11):894-900. doi: 10.1038/ncb873. PMID: 12402046
Absood A, Furutani A, Kawamura T, Graham LM. Differential PDGF secretion by graft and aortic SMC in response to oxidized LDL. Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H725-32. doi: 10.1152/ajpheart.00060.2002. PMID: 12124221 Free article.
Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, Ballard DJ, Messina LM, Gordon IL, Chute EP, Krupski WC, Busuttil SJ, Barone GW, Sparks S, Graham LM, Rapp JH, Makaroun MS, Moneta GL, Cambria RA, Makhoul RG, Eton D, Ansel HJ, Freischlag JA, Bandyk D; Aneurysm Detection and Management Veterans Affairs Cooperative Study Group. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002 May 9;346(19):1437-44. doi: 10.1056/NEJMoa012573. PMID: 12000813 Free article.
Possible Target Identified to Prevent Recurrent Blood Vessel Blockages Following Vascular Procedures
The TRPC6 gene plays a role in arterial healing after an injury, according to a new study led by Dr. Graham. This could lead to the development of therapies to reduce the occurrence of intimal hyperplasia and stenosis.